Tissue plasminogen activator (TPA or tPA) is the only effective treatment for ischemic stroke and, it also reduces mortality for patients with acute myocardial infarction. (Donnan G A, Davis S M, Parsons M W, Ma H, Dewey H M, Howells D W. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol. 2011; 7:400-409.) However, TPA treatment significantly increases the risk of serious or fatal bleeding. Intracranial bleeding after TPA therapy can be devastating and roughly 1% of patients treated with TPA for stroke will experience severely disabling or fatal hemorrhage. (Saver J L. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke. 2007; 38:2279-2283.) Similarly, 0.9-1.0% of patients given TPA for myocardial infarction develop intracranial hemorrhage and more than 50% of patients die. (Gurwitz J H, Gore J M, Goldberg R J, et al. Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2. Ann Intern Med. 1998; 129:597-604.) Although bleeding complications are often seen in older adults, children are also at significant risk of bleeding from TPA. (Gupta A A, Leaker M, Andrew M, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr. 2001; 139:682-688.) Fear of bleeding complications has diminished the therapeutic administration of TPA to patients who might otherwise benefit. (Saver J L. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke. 2007; 38:2279-2283.)
Once TPA-induced hemorrhage occurs there is no specific TPA inhibitor or antidote available to treat the bleeding. In an effort to restore coagulation, patients are frequently given cryoprecipitate, fresh frozen plasma, and platelets without conclusive evidence of efficacy. (Morgenstern L B, Hemphill J C, 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010 41:2108-2129.) Antifibrinolytic agents such as, tranexamic acid, ε-aminocaproic acid, aprotinin and novel plasmin inhibitors have also been used, but to a limited extent. Unfortunately, these agents not only inhibit the plasminogen (Pg) activation system, but also interfere with other molecular pathways. For example, aprotinin affects plasmin activity as well as the kallikrein system and, has been associated with severe allergies. (Munoz J J, Birkmeyer N J, Birkmeyer J D, O'Connor G T, Dacey U. Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery a meta-analysis. Circulation. 1999; 99:81-89.)
The mechanisms responsible for TPA bleeding are still poorly understood. By comparison to streptokinase, activation of Pg by TPA is markedly amplified by fibrin and this distinguishing property of TPA was predicted to increase fibrinolysis without increasing bleeding complications. However, excessive plasmin generation by TPA may degrade clotting factors in the circulation which affects coagulation and may enhance bleeding in vivo. TPA is a multidomain molecule that functions through both catalytic and non-catalytic interactions. There is experimental evidence that non-catalytic actions of TPA (e.g., those not causing plasminogen activation) cause breakdown of the blood brain barrier and are responsible for some of TPA's neurotoxic effects. As such, it is unclear whether TPA-induced brain hemorrhage requires the catalytic activity of TPA. TPA therapy is beneficial in ischemic stroke and myocardial infarction, but in some patients it is complicated by serious or fatal bleeding in the brain and at other sites. Fear of TPA-induced bleeding has limited the therapeutic use of TPA. In humans, TPA-induced hemorrhage and adverse outcomes are more frequent after prolonged ischemia. Similarly, in experimental stroke, after prolonged ischemia, TPA reproducibly causes brain hemorrhage, breakdown of the blood brain barrier and enhanced neuronal cell death.
In non-thrombotic models of stroke there is evidence that TPA may exert toxic effects through mechanisms, such as PDGF-CC cleavage, etc. that do not require plasminogen activation or affect fibrinolytic activity. (Su E J, Fredriksson L, Geyer M, et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med. 2008; 14:731-737.) Under pathological conditions like myocardial ischemia and stroke, the fibrinolytic activity of therapeutic TPA is enhanced by increased levels of circulating fibrin fragments (e.g., D-dimer), which may enhance the bleeding process. (Barber M, Langhorne P, Rumley A, Lowe G D, Stott D J. D-dimer predicts early clinical progression in ischemic stroke: confirmation using routine clinical assays. Stroke. 2006; 37: 1113-1115.)